Discovery of [cis-3-({(5R)‑5-[(7-Fluoro-1,1-dimethyl-2,3-dihydro‑1H‑inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)‑yl}carbonyl)­cyclobutyl]­acetic Acid (TAK-828F) as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor γt Inverse Agonist

• Published in: Journal of medicinal chemistry 2018-04, Vol.61 (7), p.2973-2988
• Main Authors: Kono, Mitsunori, Ochida, Atsuko, Oda, Tsuneo, Imada, Takashi, Banno, Yoshihiro, Taya, Naohiro, Masada, Shinichi, Kawamoto, Tetsuji, Yonemori, Kazuko, Nara, Yoshi, Fukase, Yoshiyuki, Yukawa, Tomoya, Tokuhara, Hidekazu, Skene, Robert, Sang, Bi-Ching, Hoffman, Isaac D, Snell, Gyorgy P, Uga, Keiko, Shibata, Akira, Igaki, Keiko, Nakamura, Yoshiki, Nakagawa, Hideyuki, Tsuchimori, Noboru, Yamasaki, Masashi, Shirai, Junya, Yamamoto, Satoshi
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.8b00061

A series of tetrahydro­naphthyridine derivatives as novel RORγt inverse agonists were designed and synthesized. We reduced the lipophilicity of tetrahydro­isoquinoline compound 1 by replacement of the trimethylsilyl group and SBDD-guided scaffold exchange, which successfully afforded compound 7 with a lower log D value and tolerable in vitro activity. Consideration of LLE values in the subsequent optimization of the carboxylate tether led to the discovery of [cis-3-({(5R)-5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)­carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6­(5H)-yl}­carbonyl)­cyclobutyl]­acetic acid, TAK-828F (10), which showed potent RORγt inverse agonistic activity, excellent selectivity against other ROR isoforms and nuclear receptors, and a good pharmacokinetic profile. In animal studies, oral administration of compound 10 exhibited robust and dose-dependent inhibition of IL-17A cytokine expression in a mouse IL23-induced gene expression assay. Furthermore, development of clinical symptoms in a mouse experimental autoimmune encephalomyelitis model was significantly reduced. Compound 10 was selected as a clinical compound for the treatment of Th17-driven autoimmune diseases.